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P2Y12 inhibitor initiation with clopidogrel using a loading dose (LD) is no more effective in reducing ischemic events or adverse outcomes in transcatheter aortic valve implantation (TAVI) patients than initiating the therapy without a loading dose, according to research published in the American Journal of CardiologyFeb. 10.

The BRAVO-3 trial, spearheaded by George Dangas, MD, of the Icahn School of Medicine at Mount Sinai, studied the effects of preprocedural clopidogrel with an LD versus no loading dose (NLD) in 802 patients with severe aortic stenosis who were undergoing TAVI. Dangas and colleagues said incorporating an LD into clopidogrel initiation has been beneficial in the past, reducing the risk of ischemic events after coronary stenting and allowing for more rapid inhibition of platelet activation in some studies.

“The vast majority of clinicians do not treat according to the current guidelines, resulting in a very diverse pattern of drugs and combinations,” Dangas et al. wrote in AJC. “Evidence on preprocedural LD administration of clopidogrel in TAVI patients is lacking, and loading regimens are highly variable.”

For their work, the authors stratified patients according to how they received clopidogrel (36.6 percent of subjects received an LD, while 63.4 percent did not) ahead of their procedure. Administration of clopidogrel LD was left to the discretion of the treating physician, but TAVI patients were randomized to intra-procedural anticoagulation with either bivalirudin or unfractionated heparin.

Dangas and co-authors reported that P2Y12 inhibitor maintenance therapy pre-TAVI was similar in patients with LD versus NLD—28.2 percent compared to 33.1 percent, respectively. LD and NLD were both associated with a 4.1 percent incidence of major adverse CV events (MACE) including death, MI or stroke, and the two groups saw similar rates of major bleeding (8.5 percent in the LD cohort versus 7.7 percent in the NLD cohort).

“Although we found no effects of clopidogrel LD in the reduction of MACE, the strength of the clopidogrel LD may matter,” the team wrote. “In the current study, the majority of patients (86 percent) received 300 mg LD. Increasing the dosage to 600 mg increases platelet aggregation inhibition to over 40 percent, at a time to peak effect of approximately two hours (versus four to six hours), and significantly reduces the incidence of clopidogrel hyporesponsiveness. This is associated with a reduced risk of ischemic events in patients undergoing PCI.”

Dangas et al. found a higher rate of major vascular complications in LD versus NLD patients (11.9 percent and 7.1 percent, respectively), but multivariable adjustment showed clopidogrel LD didn’t affect any of the studied clinical events, including major vascular complications.

“In this analysis from the BRAVO-3 trial, clopidogrel LD versus NLD was not associated with any significant differences in ischemic or bleeding events, except for a higher incidence of vascular complications that was no longer present after multivariate adjustment,” the authors said. “Since the potential advantages of clopidogrel LD do not seem clinically relevant for early outcomes, clopidogrel LD may be safely abandoned.”